Familial Alzheimer's Disease (FAD) has recently been associated with mutations in a novel class of presumed transmembrane proteins known as presenilins (presenilin-1 (PS-1) and presenilin-2 (Ps-2)) (1,2). Currently, the only insight into the functions of PS-1 and PS-2 is amino acid sequence homology to C. elegans gene products sel-12 (approximately 50% identity) and spe-4 (approximately 26% identity). Therefore, experimentation to elucidate the functions of mutant and wild type (WT) presenilins in neurons and live animal models would be valuable; unfortunately, transfection of neurons is very inefficient and no animal model is presently available. In order to overcome these limitations, we plan to express WT and mutant PS-1 and PS-2 in primary cultured hippocampal neurons (HNs) and in the central nervous system (CNS) using recombinant replication-deficient adenovirus (AdVs) as vectors, and to determine the effects of this expression on morphology, viability, physiology and production of pathologic features and proteins associated with Alzheimer's disease (AD). Studies in the central nervous system (CNS) will involve gene delivery via stereotaxic injection in the hippocampus as well as nasal instillation of the virus.